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Babraham research provides insights how genomes are reprogrammed at the start of life

Collaboration between an international consortium of scientists from the Babraham Institute and Universities in Germany and Japan has led to a breakthrough in understanding how the genomes of mammalian embryos are reprogrammed as new life begins. The mechanisms behind this complex process have remained enigmatic for the last 10 years.

This research, however, published today in Nature Communications sheds new light on how the egg controls this process and reveals for the first time that a new type of epigenetic modification (5-hydroxymethylcytosine) appears to be vital during the earliest stages of embryo reprogramming. In addition to advancing our knowledge of reprogramming during early mammalian development, these findings may also bring insight to understanding how epigenetic changes taking place during ageing can cause disease, since many adult conditions like heart disease, diabetes, obesity, cancer and autoimmune disorders may be associated with failure of epigenetic regulation.

Professor Wolf Reik who led the study at the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) said, “This work provides exciting new insights into how epigenomes are reprogrammed in germ cells and early embryos at the beginning of life. Elucidating these mechanisms may help us to devise better strategies for making stem cell therapies a reality. Also, erasing old epigenetic marks that are inherited from parents and grandparents may be important for healthy ageing and for preventing common diseases such as diabetes or heart disease.”

Epigenetic modification of DNA, for example by methylation, enables genes to be switched on or off at different times and places. The reprogramming or ‘erasure’ of such epigenetic tags after fertilisation is essential if cells of a developing embryo are to have the potential to become any type of tissue – a characteristic known as totipotency.

Jörn Walter, Professor of Epigenetics at Saarland University in Germany who led the German team said, “In humans the DNA code is faithfully transmitted from cell to cell and over generations. However, in each individual the chromosomes undergo dramatic and essential epigenomic changes during development. These changes do not alter the genes but affect their interpretation in all cells of a human body. Our work helps to understand the molecular signals and switches that are important in epigenetic programming and ensuring correct development.”

Shortly after fertilisation, the egg starts the unpacking and epigenetic decoding of the sperm’s chromosomes. This maternal “dominance” over the male-derived chromosomes was discovered ten years ago by the authors. A major early event governing the reprogramming is the loss of an epigenetic chemical tag called 5-methylcytosine (5mC). However, there is a striking difference between the demethylation of maternally and paternally-derived chromosomes in the fertilised eggs; the maternal genome appears to protect itself and resist demethylation.

The team discovered that the appearance of 5-hydroxymethylcytosine (5hmC) has a critical role in the process and is associated with structural reorganisation in the nucleus after fertilisation. Within the first hours of development, a strong accumulation of the novel modification 5hmC was seen, almost exclusively on male chromosomes. The egg produces an enzyme called Tet3, which drives the conversion of 5mC into 5hmC. The authors showed that removing this enzyme in the fertilised egg using RNAi methods dramatically decreased the conversion of 5mC into 5hmC. These findings also link the loss of 5mC, first observed by the authors 10 years ago, to its conversion to 5hmC.

The authors also discovered a ‘protection factor’, a protein called PGC7, which guards maternal chromosomes against the modification, while allowing “decoding” of the paternal DNA-methylation tags by modification into 5hmC. Without PGC7, the methyl groups on maternal chromosomes become accessible for hydroxylation. While the precise biological role of the large-scale conversion of 5mC into 5hmC remains unclear, the insights are likely to have wide implications for our general understanding of epigenetic reprogramming. It is known that external factors in the environment, or for example in our diet, may have consequences later in life or on future generations.

Epigenetics is now established as the ‘integrator’ between the environment and the genome so understanding how epigenomes are modified is key to understanding the mechanisms underpinning lifelong health. The Babraham Institute undertakes world-leading life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The work was supported by the BBSRC, the MRC, University of Cambridge, a grant from Deutsche Forschungsgemeinschaft, an EMBO long-term Fellowship and by the EPIGENOME Network of Excellence. One of the Babraham authors, Dr Joana Marques, was recently awarded one of the L’Oréal ‘Medals of Honor’ for Women in Science. This award aims to improve the position of women in science by recognising outstanding women researchers who have contributed to scientific progress.

About the Babraham Institute:
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.

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